JP5281890B2 - N- (heteroaryl) -1-heteroarylalkyl-1H-indole-2-carboxamide derivatives, their preparation and their use - Google Patents

Description

  The present invention relates to compounds derived from N- (heteroaryl) -1-heteroarylalkyl-1H-indole-2-carboxamides. This compound exhibits antagonistic activity in vitro and in vivo against TRPV1 (or VR1) type receptors.

  The first subject of the present invention relates to compounds corresponding to the following general formula (I):

  Another subject of the invention relates to a process for the preparation of compounds of general formula (I).

  Another subject of the invention relates to the use of the compounds of general formula (I), in particular in medicaments or pharmaceutical compositions.

  The compounds of the present invention have the general formula (I)

［式中、
Ｘ_１、Ｘ_２、Ｘ_３およびＸ_４は、互いに独立して、水素もしくはハロゲン原子またはＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、Ｃ_１〜Ｃ_６−アルコキシル、Ｃ_１〜Ｃ_６−フルオロアルコキシル、シアノ、Ｃ（Ｏ）ＮＲ_１Ｒ_２、ニトロ、ＮＲ_１Ｒ_２、Ｃ_１〜Ｃ_６−チオアルキル、−Ｓ（Ｏ）−Ｃ_１〜Ｃ_６−アルキル、−Ｓ（Ｏ）_２−Ｃ_１〜Ｃ_６−アルキル、ＳＯ_２ＮＲ_１Ｒ_２、ＮＲ_３ＣＯＲ_４、ＮＲ_３ＳＯ_２Ｒ_５もしくはアリール基（このアリールは、ハロゲンおよびＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、Ｃ_１〜Ｃ_６−アルコキシル、Ｃ_１〜Ｃ_６−フルオロアルコキシル、ニトロまたはシアノ基から選択される１つまたは複数の置換基で置換されていてもよい。）を表し；
Ｗは、窒素原子に位置１、２、３または４で結合している式

[Where:
X ₁ , X ₂ , X ₃ and X ₄ are independently of each other a hydrogen or halogen atom or C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ - _alkylene, C 1 -C ₆ - _fluoroalkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - fluoro alkoxyl, _{cyano, C (O) NR 1 R} 2, nitro, _NR 1 _{R 2} , _C 1 ~C ₆ - _{thioalkyl, -S (O) -C 1 ~C} 6 - _{alkyl, -S (O) 2 -C 1} ~C 6 - _{alkyl, SO 2 NR 1 R 2,} NR 3 COR 4, NR ₃ SO ₂ R ₅ or aryl group (the aryl are halogen and _C 1 -C ₆ - _alkyl, C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ - cycloalkyl _-C 1 -C ₃ - alkyl _Emissions, C 1 -C ₆ - _fluoroalkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - fluoro alkoxyl, optionally substituted with one or more substituents selected from nitro or cyano group .)
W is a formula bonded to the nitrogen atom at position 1, 2, 3 or 4

の縮合二環式基を表し；
Ａは、Ｏ、ＳおよびＮから選択される１個から３個のヘテロ原子を含む５〜７員ヘテロ環を表し；
Ａの炭素原子（複数も）は、水素原子およびＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、アリール、アリール−Ｃ_１〜Ｃ_６−アルキレン、オキソまたはチオ基から選択される１つまたは複数の基で置換されていてもよく；
Ａの窒素原子（複数も）は、この窒素が、オキソ基で置換された炭素原子に隣接する場合はＲ_６で、またはその他の場合はＲ_７で置換されていてもよく；
ｎは、１、２または３であり；
Ｙは、ハロゲン原子およびＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、ヒドロキシル、Ｃ_１〜Ｃ_６−アルコキシ、Ｃ_１〜Ｃ_６−フルオロアルコキシ、シアノ、Ｃ（Ｏ）ＮＲ_１Ｒ_２、ニトロ、ＮＲ_１Ｒ_２、Ｃ_１〜Ｃ_６−チオアルキル、ＳＨ、−Ｓ（Ｏ）−Ｃ_１〜Ｃ_６−アルキル、−Ｓ（Ｏ）_２−Ｃ_１〜Ｃ_６−アルキル、ＳＯ_２ＮＲ_１Ｒ_２、ＮＲ_３ＣＯＲ_４、ＮＲ_３ＳＯ_２Ｒ_５、アリール−Ｃ_１〜Ｃ_６−アルキレンまたはアリール基（このアリールおよびアリール−Ｃ_１〜Ｃ_６−アルキレンは、ハロゲンおよびＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、Ｃ_１〜Ｃ_６−アルコキシ、Ｃ_１〜Ｃ_６−フルオロアルコキシ、ニトロまたはシアノ基から選択される１個または複数個の置換基で置換されていてもよい。）から選択される１個または複数個の基で置換されていてもよいヘテロアリールを表し；
Ｒ_１およびＲ_２は、互いに独立して、水素原子またはＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、アリール−Ｃ_１〜Ｃ_６−アルキレンまたはアリール基を表し；またはＲ_１およびＲ_２は、これらが結合されている窒素原子と一緒になってアゼチジニル、ピロリジニル、ピペリジル、アゼピニル、モルホリニル、チオモルホリニル、ピペラジニルまたはホモピペラジニル基を形成しており、この基は、Ｃ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、アリール−Ｃ_１〜Ｃ_６−アルキレンまたはアリール基で置換されていてもよく；
Ｒ_３およびＲ_４は、互いに独立して、水素原子またはＣ_１〜Ｃ_６−アルキル、アリール−Ｃ_１〜Ｃ_６−アルキレンもしくはアリール基を表し；
Ｒ_５は、Ｃ_１〜Ｃ_６−アルキル、アリール−Ｃ_１〜Ｃ_６−アルキレンまたはアリール基を表し；
Ｒ_６は、水素原子またはＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、アリール−Ｃ_１〜Ｃ_６−アルキレンもしくはアリール基を表し；
Ｒ_７は、水素原子またはＣ_１〜Ｃ_６−アルキル、Ｃ_３〜Ｃ_７−シクロアルキル、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン、Ｃ_１〜Ｃ_６−フルオロアルキル、アリール−Ｃ_１〜Ｃ_６−アルキレン、Ｃ_１〜Ｃ_６−アルキル−Ｃ（Ｏ）−、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン−（ＣＯ）−、Ｃ_１〜Ｃ_６−フルオロアルキル−Ｃ（Ｏ）−、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ（Ｏ）−、アリール−Ｃ（Ｏ）−、アリール−Ｃ_１〜Ｃ_６−アルキレン−Ｃ（Ｏ）−、Ｃ_１〜Ｃ_６−アルキル−Ｓ（Ｏ）_２−、Ｃ_１〜Ｃ_６−フルオロアルキル−Ｓ（Ｏ）_２−、Ｃ_３〜Ｃ_７−シクロアルキル−Ｓ（Ｏ）_２−、Ｃ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン−Ｓ（Ｏ）_２−もしくはアリール−Ｃ_１〜Ｃ_６−アルキレン−Ｓ（Ｏ）_２−もしくはアリール基を表す。］
に一致する。

Represents a fused bicyclic group of
A represents a 5-7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S and N;
The carbon atom (s) of A are a hydrogen atom and C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene, C _1- Optionally substituted with one or more groups selected from C ₆ -fluoroalkyl, aryl, aryl-C ₁ -C ₆ -alkylene, oxo or thio groups;
The nitrogen atom (s) of A may be substituted with R ₆ when the nitrogen is adjacent to a carbon atom substituted with an oxo group, or with R ₇ otherwise;
n is 1, 2 or 3;
Y is a halogen atom and _C 1 -C ₆ - _alkyl, C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ - cycloalkyl _-C 1 -C ₃ - _alkylene, C 1 -C ₆ - fluoroalkyl, hydroxyl , C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -fluoroalkoxy, cyano, C (O) NR ₁ R ₂ , nitro, NR ₁ R ₂ , C ₁ -C ₆ -thioalkyl, SH, —S (O ) _-C 1 _{~C 6} - _{alkyl, -S (O) 2 -C 1} ~C 6 - _{alkyl, SO 2 NR 1 R 2,} NR 3 COR 4, NR 3 SO 2 R 5, aryl _-C 1 -C ₆ - alkylene or aryl group (the aryl and aryl _-C 1 -C ₆ - alkylene, halogen and _C 1 -C ₆ - _alkyl, C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ - A cycloalkyl _-C 1 -C ₃ - _alkylene, C 1 -C ₆ - _fluoroalkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - fluoroalkoxy, one or more selected from nitro or cyano group A heteroaryl which may be substituted with one or more groups selected from:
R ₁ and R ₂ are each independently a hydrogen atom or C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene, aryl -C ₁ -C ₆ -alkylene or aryl group; or R ₁ and R ₂ together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl forms a group, this group _is, C 1 -C ₆ - _alkyl, C 3 -C ₇ - _cycloalkyl, C 3 -C ₇ - cycloalkyl _-C 1 -C ₃ - alkylene, aryl _-C 1 ~ Optionally substituted with a C ₆ -alkylene or aryl group;
R ₃ and R ₄ independently of one another represent a hydrogen atom or a C ₁ -C ₆ -alkyl, aryl-C ₁ -C ₆ -alkylene or aryl group;
R ₅ represents a C ₁ -C ₆ -alkyl, aryl-C ₁ -C ₆ -alkylene or aryl group;
R ₆ is a hydrogen atom or C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene, C ₁ -C ₆ -fluoroalkyl, Represents an aryl-C ₁ -C ₆ -alkylene or aryl group;
R ₇ is a hydrogen atom or C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene, C ₁ -C ₆ -fluoroalkyl, Aryl-C ₁ -C ₆ -alkylene, C ₁ -C ₆ -alkyl-C (O) —, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene- (CO) —, C ₁ -C ₆ - fluoroalkyl _{-C (O) -, C 3} ~C 7 - cycloalkyl -C (O) -, aryl--C (O) -, aryl _-C 1 -C ₆ - alkylene -C (O) -, C ₁ -C ₆ - alkyl _{-S (O) 2 -, C} 1 ~C 6 - fluoroalkyl _{-S (O) 2 -, C} 3 ~C 7 - cycloalkyl _{-S (O) 2 -, C} 3 ~ C ₇ - cycloalkyl _-C 1 -C ₃ - alkylene -S (O ₂ - or aryl _-C 1 -C ₆ - represents a or aryl group - alkylene -S _{(O) 2.} ]
Matches.

In the compound of general formula (I):
The sulfur atom (s) of heterocycle A or heterocycle Y may be in oxidized form (S (O) or S (O) ₂ );
The nitrogen atom (s) of heterocycle A or heterocycle Y may be in oxidized form (N-oxide).

  Examples of groups W that may be mentioned in connection with the present invention include indolyl, isoindolyl, indolinyl, isoindolinyl, benzofuryl, dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl, benzoxazolyl, dihydrobenzoxa Zolinyl, isobenzofuranyl, dihydroisobenzofuryl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl, tetrahydroquino Ril, isoquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, Nazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenzo [b] azepinyl, tetrahydrobenzo [c] Azepinyl, tetrahydrobenzo [d] azepinyl, tetrahydrobenzo [b] [1,4] diazepinyl, tetrahydrobenzo [e] [1,4] diazepinyl, tetrahydrobenzo [b] [1,4] oxaazepinyl or tetrahydrobenzo [b] [1,4] thiazepinyl group is mentioned.

Among the compounds of general formula (I) that are the subject of the present invention, the first subgroup of compounds is that X ₁ , X ₂ , X ₃ and X ₄ are independently of one another hydrogen or halogen atoms (eg fluorine atom) or _C 1 -C ₆ - consisting of a compound represents a fluoroalkyl group (e.g., trifluoromethyl group) - alkyl groups (eg t- butyl group) or a _C 1 -C _6.

Among the compounds of general formula (I) that are the subject of the present invention, a second subgroup of compounds is that X ₁ , X ₂ , X ₃ and X ₄ are independently of one another hydrogen or halogen atoms (eg Represents a fluorine atom) or a C ₁ -C ₆ -alkyl group (eg t-butyl group), a C ₁ -C ₆ -fluoroalkyl group (eg trifluoromethyl group) or a group NR ₁ R ₂ , R ₁ and R ₂ Is the same as defined in general formula (I) (eg dimethylamine group)
Consists of compounds.

Among the compounds of general formula (I) that are the subject of the present invention, a third subgroup of compounds consists of compounds in which X ₂ is other than a hydrogen atom.

  Among the compounds of general formula (I) that are the subject of the present invention, the fourth subgroup of compounds are those in which W is attached to the nitrogen atom at position 1, 2, 3 or 4.

の縮合二環式基を表し；および
Ｗが、インドリニル、イソインドリル、イソインドリニル、ベンゾフリル、ジヒドロベンゾフリル、ベンゾチオフェニル、ジヒドロベンゾチオフェニル、ベンゾオキサゾリル、ジヒドロベンゾオキサゾリニル、イソベンゾフリル、ジヒドロイソベンゾフリル、ベンズイミダゾリル、ジヒドロベンズイミダゾリル、インドリル、インダゾリル、ベンゾチアゾリル、イソベンゾチアゾリル、ジヒドロイソベンゾチアゾリル、ベンゾトリアゾリル、キノリル、ジヒドロキノリル、テトラヒドロキノリル、イソキノリル、ジヒドロイソキノリル、テトラヒドロイソキノリル、ベンゾオキサジニル、ジヒドロベンゾオキサジニル、ベンゾチアジニル、ジヒドロベンゾチアジニル、シンノリニル、キナゾリニル、ジヒドロキナゾリニル、テトラヒドロキナゾリニル、キノキサリニル、ジヒドロキノキサリニル、テトラヒドロキノキサリニル、フタラジニル、ジヒドロフタラジニル、テトラヒドロフタラジニル、テトラヒドロベンゾ［ｂ］アゼピニル、テトラヒドロベンゾ［ｃ］アゼピニル、テトラヒドロベンゾ［ｄ］アゼピニル、テトラヒドロベンゾ［ｂ］［１，４］ジアゼピニル、テトラヒドロベンゾ［ｅ］［１，４］ジアゼピニル、テトラヒドロベンゾ［ｂ］［１，４］オキサアゼピニルまたはテトラヒドロベンゾ［ｂ］［１，４］チアゼピニル基から選択され；
該基Ｗの炭素および／または窒素原子（複数も）は、一般式（Ｉ）で定義したと同じに置換されていてもよい
化合物からなる。

And W represents indolinyl, isoindolyl, isoindolinyl, benzofuryl, dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuryl, dihydro Isobenzofuryl, benzimidazolyl, dihydrobenzimidazolyl, indolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, dihydroisoquino Ril, tetrahydroisoquinolyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroxy Zolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenzo [b] azepinyl, tetrahydrobenzo [c] azepinyl, tetrahydrobenzo [ d] azepinyl, tetrahydrobenzo [b] [1,4] diazepinyl, tetrahydrobenzo [e] [1,4] diazepinyl, tetrahydrobenzo [b] [1,4] oxaazepinyl or tetrahydrobenzo [b] [1,4] Selected from thiazepinyl groups;
The carbon and / or nitrogen atom (s) of the group W consist of compounds that may be substituted as defined in general formula (I).

Among the compounds of the fourth subgroup, the fifth subgroup of compounds is:
A formula wherein W is bonded to the nitrogen atom at position 1, 2, 3 or 4

の縮合二環式基を表し；および
Ｗが、ベンズイミダゾリルおよびインドリル基から選択され；および／または
Ａの炭素原子（複数も）は、１個または複数個のＣ_１〜Ｃ_６−アルキル基（例えばメチル）で置換されていてもよく；および／または
Ａの窒素原子（複数も）は、Ｒ_７で置換されていてもよく、Ｒ_７はＣ_１〜Ｃ_６−アルキル基（例えばメチル）を表している
化合物からなる。

And W is selected from benzimidazolyl and indolyl groups; and / or the carbon atom (s) of A is one or more C ₁ -C ₆ -alkyl groups ( for example may be substituted by methyl); and / or a nitrogen atom (s) may be substituted by R _7, R ₇ is C ₁ -C 6 _- alkyl group (e.g. methyl) It consists of the compounds represented.

Among the compounds of the fifth subgroup, the sixth subgroup of compounds is:
W is selected from benzimidazol-5-yl and indol-5-yl groups; and / or the carbon atom (s) of A are one or more C ₁ -C ₆ -alkyl groups (eg methyl ) may be substituted with; the nitrogen atom and / or a (s) may be substituted by R _7, R ₇ is C ₁ -C 6 _- represents an alkyl group (e.g. methyl) It consists of a compound.

Among the compounds of the fourth subgroup, the seventh subgroup of compounds is:
Formula where W is attached to the nitrogen atom at position 2 or 3:

の縮合二環式基を表し；および
Ｗが、ベンズイミダゾリル、インドリル、ベンゾチアゾリル、キノリル、テトラヒドロキノリルおよびベンゾオキサジニル基から選択され；および／または
Ａの炭素原子（複数も）は、１個または複数個のＣ_１〜Ｃ_６−アルキル基（例えばメチルまたはイソプロピル）、Ｃ_１〜Ｃ_６−フルオロアルキル基（例えばトリフルオロメチル基）、Ｃ_３〜Ｃ_７−シクロアルキル基（例えばシクロプロピル）またはオキソ基で置換されていてもよく；および／または
Ａの窒素原子（複数も）は、この窒素が、オキソ基で置換された炭素原子に隣接する場合はＲ_６で置換されていてもよく、Ｒ_６は水素原子またはＣ_１〜Ｃ_６−アルキル基（例えばメチル）を表しており；またはその他の場合はＲ_７で置換されていてもよく、Ｒ_７はＣ_１〜Ｃ_６−アルキル基（例えばメチル）またはＣ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン基（例えばシクロプロピルメチル）を表している
化合物からなる。

And W is selected from benzimidazolyl, indolyl, benzothiazolyl, quinolyl, tetrahydroquinolyl and benzoxazinyl groups; and / or the carbon atom (s) in A is one Or a plurality of C ₁ -C ₆ -alkyl groups (eg methyl or isopropyl), C ₁ -C ₆ -fluoroalkyl groups (eg trifluoromethyl group), C ₃ -C ₇ -cycloalkyl groups (eg cyclopropyl) Or may be substituted with an oxo group; and / or the nitrogen atom (s) of A may be substituted with R ₆ if the nitrogen is adjacent to a carbon atom substituted with an oxo group. , R ₆ represents a hydrogen atom or a C ₁ -C ₆ -alkyl group (eg methyl); or otherwise substituted with R ₇ R ₇ consists of a compound representing a C ₁ -C ₆ -alkyl group (eg methyl) or a C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene group (eg cyclopropylmethyl) .

Among the compounds of general formula (I) that are the subject of the present invention, the eighth subgroup of compounds is:
It consists of a compound in which n is 1 or 2.

Among the compounds of general formula (I) that are the subject of the present invention, the ninth subgroup of compounds is:
Y represents heteroaryl, such as pyridyl, imidazolyl, benzimidazolyl, thiazolyl or quinolyl, which heteroaryl is a C ₁ -C ₆ -alkyl group (eg methyl), NR ₁ R ₂ or aryl-C ₁ -C ₆ -May be substituted with one or more groups selected from alkylene (eg benzyl); R ₁ and R ₂ together with the nitrogen atom to which they are attached form a morpholinyl group; It consists of the compound which is.

Among the compounds of general formula (I) that are the subject of the present invention, the tenth subgroup of compounds is:
Y represents a heteroaryl selected from a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzothiazolyl, thiazolyl, furyl, quinolyl, isoquinolyl and quinoxalinyl group, which heteroaryl is a C ₁ -C ₆ -alkyl group One or more selected from (eg methyl), C ₁ -C ₆ -fluoroalkyl groups (eg trifluoromethyl group), aryl-C ₁ -C ₆ -alkylene groups (eg benzyl) or NR ₁ R ₂ R ₁ and R ₂ consist of compounds which together with the nitrogen atom to which they are attached form a morpholinyl group.

Among the compounds of general formula (I) that are the subject of the present invention, the eleventh subgroup of compounds is:
W represents a benzimidazolyl group, and the carbon and / or nitrogen atom (s) of the group W may be substituted as defined in general formula (I);
Y consists of a compound representing a pyridyl group which may be substituted in the same manner as defined in formula (I).

Among the compounds of general formula (I) that are the subject of the present invention, the twelfth subgroup of compounds is:
X ₁ , X ₂ , X ₃ and X ₄ are independently of each other hydrogen or a halogen atom (eg, a fluorine atom) or a C ₁ -C ₆ -alkyl group (eg, a t-butyl group), C ₁ -C _6- Represents a fluoroalkyl group (eg trifluoromethyl group) or NR ₁ R ₂ , wherein R ₁ and R ₂ are the same as defined in general formula (I) (eg dimethylamine group);
Formula where W is attached to the nitrogen atom at position 2 or 3:

の縮合二環式基を表し；およびＷが、ベンズイミダゾリル、インドリル、ベンゾチアゾリル、キノリル、テトラヒドロキノリルおよびベンゾオキサジニル基から選択され；
Ａの炭素原子（複数も）は、１個または複数個のＣ_１〜Ｃ_６−アルキル基（例えばメチルまたはイソプロピル）、Ｃ_１〜Ｃ_６−フルオロアルキル基（例えばトリフルオロメチル基）、Ｃ_３〜Ｃ_７−シクロアルキル基（例えばシクロプロピル）またはオキソ基で置換されていてもよく；および／または
Ａの窒素原子（複数も）は、この窒素が、オキソ基で置換された炭素原子に隣接する場合はＲ_６で置換されていてもよく、Ｒ_６は水素原子またはＣ_１〜Ｃ_６−アルキル基（例えばメチル）を表しており；またはその他の場合はＲ_７で置換されていてもよく、Ｒ_７はＣ_１〜Ｃ_６−アルキル基（例えばメチル）またはＣ_３〜Ｃ_７−シクロアルキル−Ｃ_１〜Ｃ_３−アルキレン基（例えばシクロプロピルメチル）を表しており；および／または
ｎが、１または２であり；および／または
Ｙが、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、イミダゾリル、ベンズイミダゾリル、ベンゾチアゾリル、チアゾリル、フリル、キノリル、イソキノリルおよびキノキサリニル基から選択されるヘテロアリールを表し、このヘテロアリールは、Ｃ_１〜Ｃ_６−アルキル基（例えばメチル）、Ｃ_１〜Ｃ_６−フルオロアルキル基（例えばトリフルオロメチル基）、アリール−Ｃ_１〜Ｃ_６−アルキレン基（例えばベンジル）またはＮＲ_１Ｒ_２から選択される１個または複数個の基で置換されていてもよく；Ｒ_１およびＲ_２は、これらが結合されている窒素原子と一緒になってモルホリニル基を形成している
化合物からなる。

And W is selected from benzimidazolyl, indolyl, benzothiazolyl, quinolyl, tetrahydroquinolyl and benzoxazinyl groups;
The carbon atom (s) in A are one or more C ₁ -C ₆ -alkyl groups (eg methyl or isopropyl), C ₁ -C ₆ -fluoroalkyl groups (eg trifluoromethyl group), C ₃ -C 7 _- may be substituted with a cycloalkyl group (e.g. cyclopropyl) or an oxo group; and / or nitrogen atom of a (s), the nitrogen is adjacent to a carbon atom substituted with an oxo group R ₆ may be substituted with R ₆ , R ₆ represents a hydrogen atom or a C ₁ -C ₆ -alkyl group (eg methyl); or otherwise substituted with R ₇ , _{R 7} is _C 1 -C ₆ - represents an alkylene group (e.g., cyclopropylmethyl) alkyl group (e.g. methyl) or _C 3 ~C ₇ - - cycloalkyl _-C 1 -C _3; And / or n is 1 or 2; and / or Y is heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzothiazolyl, thiazolyl, furyl, quinolyl, isoquinolyl and quinoxalinyl groups And this heteroaryl is a C ₁ -C ₆ -alkyl group (eg methyl), a C ₁ -C ₆ -fluoroalkyl group (eg trifluoromethyl group), an aryl-C ₁ -C ₆ -alkylene group (eg benzyl Or may be substituted with one or more groups selected from NR ₁ R ₂ ; R ₁ and R ₂ together with the nitrogen atom to which they are attached form a morpholinyl group. It consists of the compound which is.

Among the compounds of general formula (I) that are the subject of the present invention, the thirteenth subgroup of compounds is:
X ₁ and X ₄ each represent a hydrogen atom;
X ₂ and X ₃ each represents one of the two hydrogen atoms, and the other is a halogen atom (for example, a fluorine atom) or a C ₁ -C ₆ -alkyl group (for example, a t-butyl group), C ₁ -C _6. -Represents a group selected from fluoroalkyl (eg trifluoromethyl group) or NR ₁ R ₂ , wherein R ₁ and R ₂ are the same as defined in general formula (I) (eg dimethylamine group);
Formula where W is bonded to the nitrogen atom at position 2 or 3

の縮合二環式基を表し；およびＷが、ベンズイミダゾリル、ベンゾチアゾリル、キノリル、テトラヒドロキノリル基から選択され；
Ａの炭素原子（複数も）は、１個または複数個のＣ_１〜Ｃ_６−アルキル基（例えばメチル）で置換されていてもよく；および／または
Ａの窒素原子（複数も）は、Ｒ_７で置換されていてもよく、Ｒ_７はＣ_１〜Ｃ_６−アルキル基（例えばメチル）を表しており；
ｎが、１であり；
Ｙが、ヘテロアリール、例えばピリジル、ピラジニル、ベンゾチアゾリル、キノリル、イソキノリルまたはキノキサリニル基を表し；このヘテロアリールは、１個または複数個のＣ_１〜Ｃ_６−アルキル基（例えばメチル）またはＮＲ_１Ｒ_２で置換されていてもよく；Ｒ_１およびＲ_２は、それらが結合されている窒素原子と一緒になってモルホリニル基を形成している
化合物からなる。

And W is selected from a benzimidazolyl, benzothiazolyl, quinolyl, tetrahydroquinolyl group;
The carbon atom (s) of A may be substituted with one or more C ₁ -C ₆ -alkyl groups (eg methyl); and / or the nitrogen atom (s) of A may be R _Optionally substituted with ₇ and R ₇ represents a C ₁ -C ₆ -alkyl group (eg methyl);
n is 1;
Y represents a heteroaryl, such as a pyridyl, pyrazinyl, benzothiazolyl, quinolyl, isoquinolyl or quinoxalinyl group; the heteroaryl is one or more C ₁ -C ₆ -alkyl groups (eg methyl) or NR ₁ R ₂ R ₁ and R ₂ consist of compounds that together with the nitrogen atom to which they are attached form a morpholinyl group.

Compounds in which X ₁ , X ₂ , X ₃ , X ₄ , W, n and Y are all the same as defined in the subgroups of compounds above form the 14th subgroup.

In connection with the present invention, the following definitions apply:
C _t -C _z (where t and z can take values from 1 to 7): a carbon-based chain that can contain from t to z carbon atoms, for example C ₁ -C ₃ is 1 A carbon-based chain that may contain from 3 to 3 carbon atoms;
Alkyl: Saturated linear or branched aliphatic group. Examples that may be mentioned include groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl;
Alkylene: a saturated linear or branched divalent alkyl group, for example a C ₁ -C ₃ -alkylene group represents a linear or branched divalent carbon-based chain of 1 to 3 carbon atoms, for example methylene , Ethylene, 1-methylethylene or propylene;
Cycloalkyl: a cyclic carbon-based group. Examples that may be mentioned include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
Fluoroalkyl: an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms;
Alkoxy: the group -O-alkyl, where the alkyl group is the same as defined above;
Fluoroalkoxy: an alkoxyl group in which one or more hydrogen atoms are replaced by fluorine atoms;
Thioalkyl: the group -S-alkyl, where the alkyl group is the same as defined above;
Aryl: a cyclic aromatic group containing 6 to 10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl and naphthyl groups;
Heteroaryl: a 5- to 10-membered aromatic cyclic group containing 1 to 4 heteroatoms selected from O, S and N. Examples that may be mentioned include imidazolyl, thiazolyl, oxazolyl, furyl, thiophenyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuryl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl , Isobenzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl and quinoxalinyl groups;
Heterocycle: a saturated, partially saturated or aromatic 5- to 7-membered cyclic group containing 1 to 3 heteroatoms selected from O, S and N;
Halogen atom: fluorine, chlorine, bromine or iodine;
“Oxo” means “═O”;
“Thio” means “═S”.

  The compound of formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the present invention.

  The compounds of formula (I) may exist in the form of bases or acid addition salts. Such addition salts form part of the present invention.

  These salts are advantageously prepared with pharmaceutically acceptable acids, but other acid salts that are useful, for example, for purifying or isolating compounds of formula (I) are also part of this invention. Form.

  The compounds of general formula (I) may be in the form of hydrates or solvates, ie in the form of associations or compounds with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.

  In the rest of this specification, the term “leaving group” means a group that can be easily cleaved from a molecule by breaking a hetero bond and losing an electron pair. Thus, this group can be easily substituted with another group, for example, during a substitution reaction. Such leaving groups are, for example, halogens or activated hydroxyl groups such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate and the like. Examples of leaving groups and references for their preparation are given in “Advanceds in Organic Chemistry”, J. MoI. March, 5th Edition, Wiley Interscience, 2001.

  In accordance with the present invention, compounds of general formula (I) can be prepared by the method illustrated in Scheme 1 below.

According to Scheme 1, the compound of general formula (IV) is the same as defined for X ₁ , X ₂ , X ₃ and X ₄ in general formula (I), and B is a C ₁ -C ₆ -alkoxy group. Reacting a compound of the general formula (II) representing the compound of the general formula (III) wherein Y and n are the same as defined in the general formula (I) and GP represents a leaving group or a hydroxyl group Can be obtained by:

  Compounds of general formula (II) are commercially available or are available from literature (eg D. Knittel Synthesis 1985, 2, 186; TM Williams J. Med. Chem. 1993, 36 (9), 1291; JP 20011151771 A2). Are prepared by a number of methods described in.

  When the compound of general formula (III) is defined as n is 1, 2 or 3 and GP represents a leaving group such as a chlorine, bromine or iodine atom, the reaction is carried out with a base such as water It can be carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide or acetone in the presence of sodium oxide or potassium carbonate (n = 1: Kolasa T., Bioorg, Med. Chem. 1997, 5 (3) 507. , N = 2: Abramovitch R., Synth. Commun., 1995, 25 (1), 1).

  When the compound of general formula (III) is defined as n is 1, 2 or 3 and GP represents a hydroxyl group, the compound of general formula (IV) is the same as the compound of general formula (II) It can be obtained by reacting a compound of formula (III) in the presence of a phosphine such as triphenylphosphine and a reagent such as diethyl azodicarboxylate in solution in a solvent such as dichloromethane or tetrahydrofuran. (Q. Mitsunobu, Synthesis, 1981, 1-28).

Compounds of general formula (I), thereafter, the compound of the general formula (IV) obtained in the above general formula (V) (W is the same as defined in formula (I).) Amine compound Is reacted in a refluxing solvent such as toluene. Prior to the reaction, trimethylaluminum is allowed to act on the amine of the general formula (V).

X _{1, X} 2, _{X 3} and / or _{X 4} is formula represents cyano group, or an aryl (I), the compound (II) and _(IV), X _1, X 2, _{X 3} and / or _{X 4} A metal, for example palladium-catalyzed coupling reaction, carried out on the corresponding compound of general formula (I), (II) or (IV) in which the group represents a leaving group, for example a bromine atom, or described in the literature Or can be obtained by any other method known to those skilled in the art.

The compounds of the general formulas (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent the group C (O) NR ₁ R ₂ are X ₁ , X ₂ , X ₃ And / or the corresponding compounds of general formula (I), (II) or (IV) in which X ₄ represents a cyano group can be obtained according to methods described in the literature or known to those skilled in the art. it can.

Compounds of general formula (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent the group —S (O) -alkyl or —S (O) ₂ -alkyl are Processes described in the literature for the corresponding compounds of general formula (I), (II) or (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent a C ₁ -C ₆ -thioalkyl group Alternatively, it can be obtained by oxidation according to methods known to those skilled in the art.

Compounds of general formula (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent the group NR ₁ R ₂ , NR ₃ COR ₄ or NR ₃ SO ₂ R ₅ are From the corresponding compounds of the general formula (I), (II) or (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent a nitro group, methods described in the literature or known to the person skilled in the art Can be obtained, for example, by reduction followed by acylation or sulfonylation.

Compounds of general formula (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent the group NR ₁ R ₂ , NR ₃ COR ₄ or NR ₃ SO ₂ R ₅ are From the corresponding compounds of the general formulas (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent, for example, a bromine atom, methods described in the literature or to those skilled in the art According to known methods, it can be obtained by coupling reaction with amine, amide or sulfonamide, respectively, in the presence of a base, phosphine and palladium-based catalyst.

Compounds of the general formula (I), (II) and (IV) in which X ₁ , X ₂ , X ₃ and / or X ₄ represent the group SO ₂ NR ₁ R ₂ are described in Pharmazie 1990, 45, 346. Or according to methods described in the literature or known to those skilled in the art.

Compounds of general formula (I) in which R ₇ represents a hydrogen atom can be obtained, for example, from compounds of general formula (I) in which R ₇ represents a phenylmethyl group, by hydrogenation in the presence of a palladium-based catalyst or in the literature. It can be obtained by the methods described or known to those skilled in the art.

  As used herein, compounds of formula (III) are either commercially available or are described in the literature (Carling RW et al J. Med. Chem. 2004 (47), 1807-1822 or Russel MGN. et al. J. Med. Chem. 2005 (48), 1367-1383) or can be obtained by using methods known to those skilled in the art. Compound (V) and other reagents are commercially available when their methods of preparation are not described, or are described in the literature (eg, WO 03/049 702 and WO 03/068 749).

According to another aspect of the present invention, compounds of formula (IV _1-35 ) or (V _1-6 ) are also the subject of the present invention. These compounds are useful as intermediates for synthesizing compounds of formula (I) (more generally in preparing therapeutic compounds).

All indoles (IV _1-35 ) listed in Table 1 were prepared by one of the methods described in Scheme 1.

Table 1 below shows the chemical structure and physical properties of selected compounds of the general formula (IV _1-35 ) _{according to the} invention. In this table:
The “mp” column lists the melting point of the product in degrees Celsius (° C.);
If the product is isolated in the form of an amorphous solid or oil, they are characterized in this column by their mass ([MH] ⁺ ) or their NMR data (NMR) listed below. Has been;
t-Bu represents a t-butyl group, Me represents a methyl group, and Et represents an ethyl group.
Table 1

^* Product IV ₂₁ was obtained in the form of a mixture of three isomers. This is used in the remainder of the synthesis of (I) described in Scheme 1 without further purification to give products 94, 95 and 96 after chromatographic separation (see experimental section) I want to be.)

The NMR data for selected compounds in Table 1 are listed below.
Compound IV ₄ : ¹ H NMR (CDCl ₃ ), δ (ppm): 1.3 (t, 3H); 4.2 (q, 2H); 5.79 (s, 2H); 6.82 (d, 2H); 7.07 (m, 2H); 7.27 (m, 2H); 8.41 (d, 2H).
Compound IV ₂₄ : ¹ H NMR (CDCl ₃ ), δ (ppm): 1.38 (t, 3H); 2.6 (s, 3H); 4.32 (q, 2H); 5.91 (s, 2H); 6.39 (d, 1H); 7.05 (m, 2H); 7.35 (m, 4H).
Compound IV ₂₅ : ¹ H NMR (CDCl ₃ ), δ (ppm): 1.54 (t, 3H); 4.51 (q, 2H); 6.1 (s, 2H); 6.97 (m, 7.29 (t × d, 1H); 7.41 (m, 1H); 7.6 (m, 6H); 8.06 (m, 2H); 7.5 (d, 1H).
Compound IV ₂₆ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 1.25 (s, 9H); 3.79 (s, 3H); 5.90 (s, 2H); 6.96 (d 7.27 (d × d, 1H); 7.35 (s, 1H); 7.46 (s, 1H); 7.66 (d, 1H); 8.45 (d × d, 2H).
Compound IV ₂₇ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 1.27 (t, 3H); 4.29 (q, 2H); 5.95 (s, 2H); 6.93 (d 7.58 (s, 1H); 7.61 (d × d, 1H); 7.80 (d, 1H); 8.22 (s, 1H); 8.45 (d × d, 2H).
Compound IV ₂₈ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 1.23 (t, 3H); 2.91 (s, 6H); 4.2 (q, 2H); 5.79 (s , 2H); 6.56 (s, 1H); 6.8 (d × d, 1H); 6.94 (d × d, 2H); 7.26 (s, 1H); 7.52 (d, 1H); 8.45 (d × d, 2H).
Compound IV ₂₉ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 3.82 (s, 3H); 6 (s, 2H); 6.9 (d, 2H); 7.46 (d, 1H 7.54 (s, 1H); 7.99 (d, 1H); 8.08 (s, 1H); 8.45 (d × d, 2H).
Compound IV ₃₀ : ¹ H NMR (CDCl ₃ ), δ (ppm): 1.41 (m, 12H); 4.35 (q, 2H); 5.81 (s, 2H); 6.97 (d, 2H); 7.21 (d, 1H); 7.45 (m, 2H); 7.74 (m, 1H); 8.54 (d, 2H).
Compound IV ₃₁ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 1.25 (t, 3H); 1.32 (s, 9H); 4.25 (q, 2H); 5.88 (s) , 2H); 6.79 (d, 1H); 7.22 (m, 1H); 7.32 (s, 1H); 7.4 (m, 2H); 7.65 (m, 2H); .46 (m, 1H).
Compound IV ₃₂ : ¹ H NMR (DMSO D ₆ ), δ (ppm): 1.28 (t, 3H); 1.32 (s, 9H); 4.29 (q, 2H); 5.85 (s 7.27 (m, 1H); 7.35 (m, 2H); 7.48 (m, 2H); 7.65 (d, 1H); 8.36 (d, 1H); .41 (d, 1H).

Amines (V _1-6 ) can be prepared by the synthetic route described in Scheme 2.

In this scheme, Z ₁ and Z ₂ each independently represent a C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl or C ₃ -C ₇ -cycloalkyl-C ₁ -C ₃ -alkylene group. .

4-nitro-1,2-phenylenediamine (VI) and reagents such as wherein _Z 2 _-CO 2 H (wherein, _{Z 2} is _C 1 -C ₆ - _alkyl, C 3 -C ₇ - cycloalkyl or _{C 3} -C ₇ - can be generated benzimidazole (VII) by performing the cyclized with carboxylic acids represent) the alkylene group -. cycloalkyl _-C 1 -C _3. This product is then represented by the formula Z ₁ -GP, where GP is defined as in Scheme 1 and Z ₁ is C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl or C ₃ -C 7 _- substituting the compound of an alkylene group), such as solvents, for example bases in tetrahydrofuran, for example, group Z ₁ by reacting in the presence of sodium hydride _- cycloalkyl -C 1 _-C 3. be able to. The resulting mixture of benzimidazoles (VIII) is then converted by reduction, for example by catalytic hydrogenation in the presence of a catalyst such as palladium on activated carbon, or as known to those skilled in the art, to convert the nitro group to an amine. _Is converted to the amine (V _1-6 ) by any other method for

Amines (V _1-6 ) are listed in Tables 2a and 2b. A description of the method of preparation of one of these amines is detailed in the experimental section.
Table 2a

Table 2b

  The following examples illustrate the preparation of some compounds according to the present invention. These examples do not limit the invention, but are merely intended to illustrate the invention. The compound numbers listed as examples refer to those listed in Table 3. Elemental microanalysis, ie LC-MS analysis (liquid chromatography coupled to mass spectrometry), IR spectrum or NMR spectrum confirms the structure of the compound obtained.

(Compound 3)
N- (1-methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 1)

1.1. Ethyl 5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate was prepared in 60%. Add dropwise to 10 mL of a dimethylformamide suspension of 0.38 g (9.45 mmol) of% sodium hydride and stir at 0 ° C. under argon. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is cooled and 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide is added in small portions. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is again cooled to 0 ° C. and an additional 0.38 g (9.45 mmol) of 60% sodium hydride in 10 mL of dimethylformamide is added. After 30 minutes at 0 ° C., 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide are added in small portions. The reaction mixture is then stirred at 20 ° C. for 20 hours. After this time, the mixture is poured into a solution of 100 mL ice water and 100 mL ethyl ether. The organic phase is separated and the aqueous phase is re-extracted with 100 mL of ethyl ether. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / acetone). 0.65 g of the desired product is obtained in the form of an oil which is used in the next synthesis without further purification.

1.2 N- (1-Methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 1) (Compound 3)
1.26 mL of trimethylaluminum (2M in toluene) under argon, 0.18 g (1.21 mmol) of 5-amino-1-methyl-1H-indole (IT Forbes, J. Med. Chem. 1993, 36 Add to 10 mL of dry toluene solution of (8), 1104). After 15 minutes, 0.3 g (1.01 mmol) of ethyl 5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate obtained in step 1.1 is added. The reaction medium is refluxed for 4 hours and then stirred overnight at room temperature. This is poured onto ice and extracted twice with 30 mL of dichloromethane. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / acetone). 0.35 g of a solid is obtained, which is dried under reduced pressure.
Melting point (base): 204-205 ° C.

The resulting solid is taken up in 30 mL of dichloromethane and 0.26 mL of 4N hydrogen chloride in dioxane is added. The solution is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of isopropanol and methanol. 0.33 g of the desired product is thus obtained in the form of the hydrochloride.
Melting point (1 HCl): 258-260 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 3.76 (s, 3H); 6.1 (s, 2H); 6.33 (d, 1H); 7.11 (d × d, 1H 7.25 (d, 2H); 7.37 (m, 2H); 7.52 (m, 5H); 7.9 (s, 1H); 8.7 (d, 2H).

(Compound 4)
N- (1-Methyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrid-3-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 2)

2.1. Ethyl 5-fluoro-1-[(pyrid-3-yl) methyl] -1H-indole-2-carboxylate A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate was prepared. Add dropwise to 10 mL of a dimethylformamide suspension of 0.38 g (9.45 mmol) of 60% sodium hydride and stir at 0 ° C. under argon. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is cooled and 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide is added in portions. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is again cooled to 0 ° C. and an additional 0.38 g (9.45 mmol) of 60% sodium hydride in 10 mL of dimethylformamide is added. After 30 minutes at 0 ° C., 1.24 g (4.8 mmol) of 3-bromomethylpyridine hydrobromide are added in small portions. The reaction mixture is then stirred at 20 ° C. for 58 hours. The mixture is then poured into a solution of 100 mL ice water and 100 mL ethyl ether. The organic phase is separated and the aqueous phase is re-extracted with 100 mL of ethyl ether. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / acetone). 0.5 g of the desired product is obtained in the form of a solid, which is used in the next synthesis without further purification.
Melting point = 104-105 ° C.

2.2 N- (1-Methyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrid-3-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 2 (Compound 4)
4.1 mL of trimethylaluminum (2M in toluene) is added to 10 mL of a dry toluene solution of 0.414 g (2.82 mmol) of 5-amino-1-methyl-1H-benzimidazole under argon. After 15 minutes, 0.7 g (2.35 mmol) of ethyl 5-fluoro-1-[(pyrid-3-yl) methyl] -1H-indole-2-carboxylate from step 2.1 is added. The reaction medium is refluxed for 4 hours and then stirred overnight at room temperature. This is poured into 100 g of ice and 50 mL of dichloromethane. A suspension was obtained, which was filtered and washed with water and ether. The residue is purified by preparative chromatography on alumina (eluent: dichloromethane / methanol). 0.36 g of a solid is obtained, which is dried under reduced pressure.

The resulting solid is taken up in 30 mL of dichloromethane and 0.55 mL of 4N hydrogen chloride in dioxane is added. The solution is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of isopropanol and methanol. 0.36 g of the desired product is thus obtained in the form of the hydrochloride.
Melting point (2HCl): 268-270 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 4.03 (s, 3H); 6 (s, 2H); 7.18 (d × d, 1H); 7.56 (d × d, 1H) 7.68 (m, 2H); 7.9 (m, 4H); 8.41 (s, 1H); 8.69 (m, 2H); 9.59 (s, 1H).

(Compound 6)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-t-butyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 2)

3.1. Ethyl 5-t-butyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate 1 g (4.08 mmol) of ethyl 5-t-butyl-1H-indole-2-carboxylate The solution of Lat is added dropwise to 10 mL of a 60% sodium hydride 0.33 g (8.15 mmol) dimethylformamide suspension and stirred at 0 ° C. under argon. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is cooled and 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide is added in small portions. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 30 minutes. The reaction mixture is again cooled to 0 ° C. and an additional 0.33 g (8.15 mmol) of 60% sodium hydride in 10 mL of additional dimethylformamide is added. After 30 minutes at 0 ° C., 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide is added in small portions. The reaction mixture is then stirred at 20 ° C. for 20 hours. After this time, the mixture is poured into a solution of 100 mL ice water and 70 mL ethyl ether. The organic phase is separated and the aqueous phase is re-extracted with 50 mL of ethyl ether. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / acetone). 0.7 g of the desired product is obtained in the form of an oil, which is used in the next synthesis without further purification.

3.2 N- (1,2-Dimethyl-1H-benzimidazol-5-yl) -5-t-butyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 2) (Compound 6)
0.9 mL of trimethylaluminum (2M in toluene) is added to 20 mL of a dry toluene solution of 0.24 g (1.43 mmol) of 5-amino-1,2-dimethyl-1H-benzimidazole (WO2002059110) under argon. After 15 minutes, 0.4 g (1.19 mmol) of ethyl 5-t-butyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate from step 3.1 is added. . The reaction medium is refluxed for 4 hours and then stirred overnight at room temperature. This is poured into 150 g of ice and 70 mL of dichloromethane. The aqueous phase is separated and extracted twice with 30 mL of dichloromethane. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / methanol). 0.4 g of a solid is obtained, which is dried under reduced pressure.
Melting point (base): 270-272 ° C.

The solid obtained is taken up in 30 mL of a 9/1 mixture of dichloromethane and methanol and 0.5 mL of 4N dioxane hydrochloride solution is added. The solution is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of ethanol and water. 0.22 g of the desired product is thus obtained in the form of the hydrochloride.
Melting point (2HCl): 295-300 ° C.
NMR ¹ H (DMSO D ₆ ), δ (ppm): 1.31 (s, 9H), 2.79 (s, 3H), 3.89 (s, 3H); 6.08 (s, 2H); 7.42 (m, 4H); 7.8 (m, 4H); 8.3 (s, 1H); 8.7 (d, 2H); 10.9 (s, 1H exchangeability)

(Compound 7)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide hydrochloride (1: 2) (Compound 7)

1 mL of trimethylaluminum (2M in toluene) is added to 20 mL of a dry toluene solution of 0.27 g (1.61 mmol) of 5-amino-1,2-dimethyl-1H-benzimidazole (WO02059110) under argon. After 15 minutes, 0.4 g (1.34 mmol) of ethyl 5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate obtained in the first step of Example 1 was added. Add. The reaction medium is refluxed for 3 hours and then stirred overnight at room temperature. This is poured onto ice and extracted twice with 30 mL of dichloromethane. The organic phases are combined, washed with 50 mL water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / acetone). 0.46 g of solid is obtained, which is dried under reduced pressure.
Melting point (base): 249-250 ° C.

The resulting solid is taken up in 30 mL of dichloromethane and 0.26 mL of 4N hydrogen chloride dioxane solution is added. The solution is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of isopropanol and methanol. 0.33 g of the desired product is thus obtained in the form of the hydrochloride.
Melting point (2HCl): 285-287 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.8 (s, 3H), 3.87 (s, 3H); 6.1 (s, 2H); 7.16 (d × d, 1H 7.51 (m, 4H); 7.75 (s, 1H); 7.85 (d, 2H); 8.3 (s, 1H); 8.75 (d, 2H).

(Compound 11)
N- (1-methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrid-3-yl) ethyl] -1H-indole-2-carboxamide

5.1. 10 mL of tetrahydrofuran solution of 0.365 g (1.44 mmol) of ethyl 5-fluoro-1-[(pyrid-3-yl) ethyl] -1H-indole-2-carboxylate 1,1 ′-(azodicarbonyl) dipiperidine Of ethyl 5-fluoro-1H-indole-2-carboxylate (0.2 g, 0.97 mmol), 2- (pyrid-3-yl) ethanol (0.178 g, 1.45 mmol) and tributylphosphine (0.36 mL). Add dropwise to 30 mL of a solution of (1.44 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature overnight and then concentrated under reduced pressure and taken up in 50 mL of cyclohexane. The suspension is then filtered and the filtrate is chromatographed on a column of silica (eluent: dichloromethane / methanol). 0.125 g of the desired product is obtained.

5.2 N- (1-Methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrid-3-yl) ethyl] -1H-indole-2-carboxamide (Compound 11)
0.54 mL of trimethylaluminum (2M in toluene) was added at 0 ° C. under argon at 5-amino-1-methyl-1H-indole (IT Forbes, J. Med. Chem. 1993, 36 (8), 1104. ) Add to 5 mL of 0.7 g (0.478 mmol) dry toluene solution. After 15 minutes, 0.125 g (0.4 mmol) of ethyl 5-fluoro-1-[(pyrid-3-yl) ethyl] -1H-indole-2-carboxylate obtained in step 5.1 is added. The reaction medium is refluxed for 5 hours and then stirred overnight at room temperature. This is poured into 50 g of ice, 10 mL of 1N hydrochloric acid and 30 mL of ethyl acetate. The organic phase is separated and 15 mL of 1N sodium hydroxide is added to the aqueous phase, which is reextracted with 30 mL of additional ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is taken up in 15 mL of isopropyl ether, and the insoluble material is filtered off and dried under reduced pressure. 50 mg of the desired product are thus isolated in the form of a solid.
Melting point (base): 188-189 ° C.
¹ H NMR (CDCl ₃ ), δ (ppm): 3.19 (t, 2H); 3.85 (s, 3H); 4.85 (t, 2H); 6.49 (d, 1H); 6 .92 (s, 1H); 7.1 (m, 3H); 7.29 (m, 4H); 7.49 (d × t, 1H); 7.75 (m, 1H); 7.9 ( s, 1H); 8.21 (d, 1H); 8.4 (d, 1H).

(Compounds 94, 95 and 96)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(3,6-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 94)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(5,6-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 95)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(3,5-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 96)

6.1. (Chloromethyl) dimethylpyrazine (mixture of three isomers)
Add 7.6 g (32.74 mmol) of trichloroisocyanuric acid to 820 mL of a solution of 10 g of dichloroethane in 10 g of trimethylpyrazine (81.85 mmol) maintained at reflux over 1 hour. The reaction mixture is refluxed for 6 hours, then cooled to 20 ° C., stirred for a further 12 hours and filtered. The filtrate is concentrated under reduced pressure, taken up in 200 mL of ethyl ether, filtered again and concentrated under reduced pressure. 9.6 g of methyldimethylpyrazine chloride is recovered in the form of a mixture, which is used in the next step without further purification.

6.2. Ethyl 5-fluoro-1-[(dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxylate (mixture of compound IV ₂₁ )
A solution of 5 g (24.13 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate was added to 1.45 g (36.2 mmol) of dimethyl 60% sodium hydride stirred at 0 ° C. under argon. Add dropwise to 200 mL formamide suspension. The mixture is stirred at 0 ° C. for 30 minutes and then at 20 ° C. for 1 hour. 9.45 g (60.33 mmol) of the mixture of methyldimethylpyrazine chloride obtained in the previous step are added in small portions. The mixture is stirred at 20 ° C. for 2 hours and then 200 mL of water and 200 mL of ethyl acetate are added. The organic phase is separated and the aqueous phase is re-extracted with 100 mL of ethyl acetate. The organic phases are combined, washed twice with 50 mL water and 50 mL saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane / ethyl acetate).

1.1 g of a mixture of the three desired isomers (IV ₂₁ ) are obtained and this product is used in the next synthesis without further purification.

6.3. N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(3,6-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 94)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(5,6-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 95)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(3,5-dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (compound 96)
Add 2.57 mL of trimethylaluminum (2M in toluene) to 20 mL of a dry toluene solution of 0.568 g (3.53 mmol) of 5-amino-1,2-dimethyl-1H-benzimidazole (WO02059110) under argon. After 15 minutes, 1.05 g (3.21 mmol) of ethyl 5-fluoro-1-[(dimethylpyrazin-2-yl) methyl] -1H-indole-2-carboxylate obtained in the previous step is added. The reaction medium is refluxed for 4 hours and then stirred overnight at room temperature. This is poured onto ice and extracted twice with 100 mL of ethyl acetate. The organic phases are combined and washed successively with 50 mL water and 50 mL saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC chromatography (eluent: ethanol / heptane / triethylamine).
The following separates:

0.59 g of isomer 94 in the form of a solid,
Melting point: 269-275 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.31 (s, 3H); 2.46 (s, 3H); 2.6 (s, 3H); 3.69 (s, 3H); 5.95 (s, 2H); 7.02 (t × d, 1); 7.4 (m, 5H); 7.86 (s, 1H); 8 (s, 1H)
0.139 g of isomer 95 in the form of a solid,
Melting point: 226-228 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.36 (s, 6H); 2.49 (s, 3H); 3.9 (s, 3H); 6.41 (s, 2H); 7.8 (t × d, 1H); 8.06 (s, 1H); 8.2 (m, 1H); 8.29 (m, 2H); 8.4 (m, 1H); 8.71 (S, 2H); 11.6 (s, 1H)
And 0.51 g of isomer 96 in solid form,
Melting point: 266-269 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.18 (s, 3H); 2.49 (s, 3H); 2.6 (s, 3H); 3.71 (s, 3H); 6.41 (s, 2H); 7.1 (t × d, 1H); 7.4 (m, 5H); 7.85 (s, 1H); 8.2 (s, 1H); 10.3 (S, 1H).

(Compound 32)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-carboxamide (Compound 32)

7.1. Ethyl 5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₁₄ )
In a manner similar to that described in Example 6.2, 1.55 g of ethyl 5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₁₄ ) Is isolated starting from 2 g (9.65 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate.
[MH] ⁺ = 300.

7.2. N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-carboxamide (Compound 32)
In a manner similar to that described in Example 6.3, N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrazin-2-yl) methyl ] -1H-indole-2-carboxamide (Compound 32) was added to ethyl 5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₁₄ ) 0. Isolate starting from 0.5 g.
Melting point: 239-240 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.5 (s, 3H); 3.7 (s, 3H); 5.98 (s, 2H); 7.11 (t × d, 1H ); 7.49 (m, 5H); 7.9 (d, 1H); 8.4 (s, 1H); 8.5 (s, 2H); 10.39 (s, 1H).

(Compound 37)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-indole-2-carboxamide (Compound 37)

8.1. Ethyl 5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₁₇ )
In a manner similar to that described in Example 6.2, ethyl 5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₁₇ ) 1 .2 g are isolated starting from 2 g (9.65 mmol) of ethyl 5-fluoro-1H indole-2-carboxylate.
[MH] ⁺ = 313.

8.2. N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-indole-2-carboxamide (Compound 37)
In a manner similar to that described in Example 6.3, N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(4-methylpyrid-2-yl ) Methyl] -1H-indole-2-carboxamide (Compound 37) 0.48 g of ethyl 5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate (Compound) IV ₁₇ ) Isolated starting from 0.51 g.
Melting point: 213-215 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.18 (s, 3H); 2.49 (s, 3H); 3.67 (s, 3H); 5.88 (s, 2H); 6.82 (s, 1H); 7.08 (m, 2H); 7.4 (m, 5H); 7.9 (s, 1H); 8.39 (s, 1H); 10.4 (s , 1H).

(Compound 67)
N- (1-methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrimido-4-yl) methyl] -1H-indole-2-carboxamide (Compound 67)

9.1. Ethyl 5-fluoro-1-[(pyrimido-4-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₃₅ )
2.6 g ethyl 5-fluoro-1-[(pyrimid-4-yl) methyl] -1H-indole-2-carboxylate (compound IV ₃₅ ) by a method similar to that described in Example 6.2 Is isolated starting from 3.3 g (15.93 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate.
[MH] ⁺ = 300.

9.2. N- (1-methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrimido-4-yl) methyl] -1H-indole-2-carboxamide (Compound 67)
In a manner similar to that described in Example 6.3, N- (1-methyl-1H-indol-5-yl) -5-fluoro-1-[(pyrimid-4-yl) methyl] -1H -0.41 g of indole-2-carboxamide (compound 67) from 0.5 g of ethyl 5-fluoro-1-[(pyrimido-4-yl) methyl] -1H-indole-2-carboxylate (compound IV ₃₅ ) Isolate starting.
Melting point: 199-200 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.5 (s, 3H); 3.69 (s, 3H); 5.93 (s, 2H); 6.91 (d, 1H); 7.08 (t × d, 1H); 7.42 (m, 5H); 7.85 (s, 1H); 8.62 (d, 1H); 9.03 (s, 1H); 10.31 (S, 1H).

(Compound 68)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (Compound 68)

10.1. Ethyl 5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₂₂ )
In a manner similar to that described in Example 6.2, ethyl 5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₂₂ ) 0.32 g is isolated starting from 3.3 g (15.93 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate.
[MH] ⁺ = 314.

10.2. N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-indole-2-carboxamide (Compound 68)
In a manner similar to that described in Example 6.3, N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(6-methylpyrazin-2- Yl) methyl] -1H-indole-2-carboxamide (Compound 68) was added to ethyl 5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-indole-2-carboxylate. (Compound IV ₂₂ ) Isolated starting from 0.38 g.
Melting point: 244-249 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.39 (s, 3H); 2.49 (s, 3H); 3.69 (s, 3H); 5.91 (s, 2H); 7.08 (m, 1H); 7.42 (m, 5H); 7.9 (s, 1H); 7.99 (s, 1H); 8.36 (s, 1H).

(Compound 24)
N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide (Compound 24)

11.1. Ethyl 5-trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate (Compound IV ₂₇ )
50 mL of a toluene solution of 1.47 g (5.83 mmol) of 1,1 ′-(azodicarbonyl) dipiperidine was added to 1 g (3.89 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate, 4 -Add dropwise to 50 mL of a toluene solution of 0.63 g (5.83 mmol) of pyridylcarbinol and 1.46 mL (5.83 mmol) of tributylphosphine. The reaction mixture is stirred overnight at room temperature, then concentrated under reduced pressure and chromatographed on a column of silica (eluent: dichloromethane / methanol). 1.05 g of the desired product is obtained.
¹ H NMR (DMSO D ₆ ), δ (ppm): 1.27 (t, 3H); 4.29 (q, 2H); 5.95 (s, 2H); 6.93 (d, 2H); 7.58 (s, 1H); 7.61 (d × d, 1H); 7.80 (d, 1H); 8.22 (s, 1H); 8.45 (d × d, 2H).

11.2. N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide (Compound 24)
In a manner similar to that described in Example 6.3, N- (1,2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1-[(pyrid-4-yl ) Methyl] -1H-indole-2-carboxamide (compound 24) 0.65 g of ethyl 5-trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate (compound IV ₂₇ ) Isolated starting from 0.5 g.
Melting point: 250-251 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 2.49 (s, 3H); 3.69 (s, 3H); 5.95 (s, 2H); 6.98 (d, 1H); 7.49 (m, 4H); 7.69 (d, 1H); 7.9 (s, 1H); 7.99 (s, 1H); 8.19 (s, 1H); 8.42 (d , 2H).

(Compound 91)
N- (2-cyclopropyl-1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide (Compound 91)

12.1.2-Cyclopropyl-5-nitro-1H-benzimidazole In the same manner as described in the literature (WO 96/04270), 5 g (32.65 mmol) of 4-nitro-1,2-phenylenediamine 77 mL (0.979 mol) of cyclopropanecarboxylic acid solution is stirred at reflux for 14 hours. The reaction mixture is then concentrated under reduced pressure and taken up in 150 mL of ethyl acetate and 100 mL of sodium bicarbonate. The organic phase is washed with 100 mL of water and then with 50 mL of saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. 6.5 g of a brown oil are obtained and used in the next step without further purification.

12.2.2-Cyclopropyl-1-methyl-5-nitro-1H-benzimidazole and 2-cyclopropyl-1-methyl-6-nitro-1H-benzimidazole 2-cyclopropyl obtained in the previous step 20 mL of a tetrahydrofuran solution of 6.5 g (32 mmol) of -5-nitro-1H-benzimidazole is added dropwise to 150 mL of a stirred suspension of 2.6 g sodium hydride (63.98 mmol) under argon at room temperature. . The reaction mixture is stirred for 3 hours at 20 ° C. and 2.2 mL (35.2 mmol) of methyl iodide are then added. Stirring is continued for a further 48 hours. The reaction mixture is then concentrated under reduced pressure and then chromatographed directly on a column of silica (eluent: dichloromethane / methanol). 4.5 g of the desired isomer mixture is thus obtained in the form of a solid, which is used in the next step without further purification.

12.3. 2-Cyclopropyl-1-methyl-5-amino-1H-benzimidazole (compound V ₂ ) and 2-cyclopropyl-1-methyl-6-amino-1H-benzimidazole (compound V ₅ )
15 g of ammonium formate (0.236 mol) is added to 50 mL of ethanol suspension of 0.3 g of palladium on 10% activated charcoal stirred at 20 ° C. This first reactor was mixed with 2-cyclopropyl-1-methyl-5-nitro-1H-benzimidazole and 2-cyclopropyl-1-methyl-6-nitro-1H-benzimidazole obtained in the previous step. To a second reactor in which 130 mL of an ethanol suspension of 4.5 g (20.7 mmol) of the mixture and 0.4 g of palladium on 10% activated carbon is vigorously stirred at 20 ° C.

After stirring at 20 ° C. for 48 hours, 15 g (0.236 mol) of ammonium formate, 0.3 g of 10% palladium on charcoal and 50 mL of ethanol are added to the mixture, which is stirred for a further 24 hours and then passed through a plug of celite. Filter and concentrate under reduced pressure to give 4 g of an oil, which is purified by HPLC.
The following separates:
1.1 g of product V ₂ ,
[MH] ⁺ = 188
¹ H NMR (DMSO D ₆ ), δ (ppm): 1.05 (m, 4H); 2.25 (m, 1H); 3.81 (s, 3H); 6.61 (d × d, 1H) 6.72 (s, 1H); 7.26 (d, 1H)
0.92 g of product V ₅ ,
[MH] ⁺ = 188
¹ H NMR (DMSO D ₆ ), δ (ppm): 1.02 (m, 4H); 2.2 (m, 1H); 3.71 (s, 3H); 6.5 (d × d, 1H ); 6.61 (s, 1H); 7.19 (d, 1H).

12.4. N- (2-cyclopropyl-1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxamide (Compound 91)
1.26 mL of a 2N solution of trimethylaluminum in toluene was stirred under 0 ° C. of 0.376 g (2.01 mmol) of 2-cyclopropyl-1-methyl-5-amino-1H-benzimidazole (V ₂ ). Add dropwise to 70 mL of toluene solution. The mixture was then held at 50 ° C. for 15 minutes before cooling and ethyl 5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate obtained in step 1.1. 0.5 g (1.68 mmol) is then added in small portions. The mixture is stirred at reflux for 14 hours and then cooled. Add 15 mL of water followed by 25 mL of 1N hydrochloric acid solution. The pH of the resulting solution is brought to pH> 8 by adding concentrated sodium hydroxide. The solid is filtered off and taken up in 200 mL ethyl acetate and 100 mL water. The organic phase is separated, dried over magnesium sulfate, concentrated under reduced pressure and then chromatographed (eluent: dichloromethane / methanol) to give 0.3 g of the desired product 91.
Melting point = 260-261 ° C.
¹ H NMR (DMSO D ₆ ), δ (ppm): 1 (m, 4H); 2.19 (m, 1H); 3.82 (s, 3H); 5.9 (s, 2H); 02 (d, 2H); 7.12 (txd, 1H); 7.47 (m, 5H); 7.82 (d, 1H); 8.42 (d, 2H).

Table 3 below shows the chemical structure and physical properties of selected compounds of general formula (I) according to the present invention. In this table:
The “mp” column lists the melting point of the product in degrees Celsius (° C.);
In the “Salt / Base” column, “−” indicates that the compound is in the form of the free base, “HCl” indicates that the compound is in the form of the hydrochloride, and the ratio in () is (acid: Base) ratio;
t-Bu represents a t-butyl group, and Me represents a methyl group.
Table 3

  In vitro and in vivo pharmacological studies on the compounds of the present invention have demonstrated their value as substances with therapeutic activity.

  The compounds of the present invention also exhibit water solubility characteristics that favor good in vivo activity.

Inhibition of capsaicin-induced currents against rat DRG-primary culture of rat dorsal root ganglion (DRG) cells:
DRG neurons spontaneously express the TRPV1 receptor.

Newborn rat DRG primary cultures are prepared using 1-day-old rats. Briefly, after incision, the ganglia are trypsinized and the cells are isolated by mechanical grinding. Cells were resuspended in Eagle basal culture medium containing 10% fetal calf serum, 25 mM KCl, 2 mM glutamine, 100 μg / mL gentamicin and 50 ng / mL NGF, then laminin-coated glass slides (0.00 per slide). 25 × 10 ⁶ cells) and then placed in a Corning 12-well dish. Cells are incubated at 37 ° C. in a humidified atmosphere containing 5% CO ₂ and 95% air. To prevent the growth of non-neuronal cells, cytosine β-D-arabinoside (1 μM) is added after 48 hours in culture. After culturing for 7-10 days, the slides are transferred into an experimental chamber for patch clamp experiments.

Electrophysiological analysis:
A measurement chamber (volume 800 μL) containing a cell sample is placed on a moving table surface of an inverted microscope (Olympus IMT2) equipped with an Hoffman optical system (Modulation Contrast, New York) and observed at a magnification of 400 ×. . The chamber is continuously gravity flowed (2.5 mL / min) using a solution distributor that accepts 8 inlets, and its sole outlet consisting of a polyethylene tube (caliber 500 μm) is 3 mm from the cells under experiment. Place it below. A “hole cell” arrangement of patch clamps was used. A borosilicate glass pipette (resistance 5-10 mOhm) is brought to the cell by a 3D piezoelectric micromanipulator (Burleigh, PC1000). The total current (membrane potential set to −60 mV) is recorded by an Axopatch 1D amplifier (Axon Instruments, Foster City, California) connected to a PC running Pclamp8 software (Axon Instrument). The current plot points are recorded on paper and digitized (sampling frequency 15-25 Hz) and stored in the PC hard drive.

  Application of 300 nM capsaicin solution induces invading cation currents in DRG cells (voltage set to -70 mV). In order to minimize receptor desensitization, the interval between two applications of capsaicin is kept to a minimum of 1 minute. After a control period (capsaicin sensitive only stabilization), the test compound is applied alone at a given concentration (10 nM or 1 nM concentration) for 4-5 minutes, during which several capsaicin + compound tests are performed. Do (to get maximum suppression). Results are expressed as percentage inhibition of control capsaicin sensitivity.

  The percentage of inhibition of capsaicin sensitivity (300 nM) is 20% to 100% for most active compounds of the present invention tested at concentrations of 10 nM to 0.1 nM. (See the example in Table 4).

  The compounds of the invention are thus effective in vitro antagonists of TRPV1 type receptors.

Mouse Corneal Stimulation Test The stimulatory properties of capsaicin are easily evaluated on the cornea. The reason for this is that this organ is one of the organs in which C fibers are most nerve-distributed. In this context, from preliminary experiments, the application of a trace amount of capsaicin to the surface of the animal's cornea (2 μL at a concentration of 160 μM) results in several idiosyncratic behavioral characteristics associated with stimulation (this is Easily recorded.) Among these, the following are noted: blinking eyes, rubbing instilled eyes with ipsilateral forefoot, rubbing face with both forelimbs, scratching ipsilateral face with hind legs. The duration of this behavior does not exceed the 2 minute observation, and then the animal returns to its normal activity. This appearance is even more normal. The mice do not stand upside down with their hair upside down and show no observable signs of pain. It can be concluded that the duration of action of capsaicin at such doses is less than 2 minutes.

Method summary:
The basis of a series of experiments is to determine whether the compounds of the invention can affect the behavioral response elicited by a given amount of capsaicin. Capsaicin is first diluted to 25 mM in DMSO and for its final use, diluted to 10% in saline in Tween 80. Control experiments show that the solvent has no effect under these conditions.

  In practice, the test product is administered orally and the animal is given 2 μL of a 160 μM capsaicin solution prepared as described above with a delay time (pretreatment time: t) determined by pharmacokinetic data. Give an eye drip. The number of times the instilled eye is rubbed with the ipsilateral forefoot during the 2 minute observation after the infusion is recorded.

For a given animal, the percentage of protection is calculated as follows:
P = 100 − ((number of observed scratching operations / average number of scratching operations for the group treated with solvent) × 100)
This percentage of protection is averaged for each group of animals (n = number of animals tested with compounds of the invention).

  The percentage of protection evaluated in this model was 20% to 100% for most active compounds of the present invention used at a dose of 1 mg / kg (oral) (selected examples in Table 5). Please refer.)

  The results of these tests show that most active compounds of the invention block the effects induced by stimulating the TRPV1 receptor.

  The compounds of the invention can thus be used for the preparation of a medicament, in particular for the preparation of a medicament for the prevention or treatment of diseases in which the TRPV1 receptor is involved.

  Thus, according to another aspect of the present invention, the subject of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt of said compound or another form of hydrate or solvate. Contains drugs.

  Therapeutic uses of these drugs are in particular pain and inflammation, chronic pain, neuropathic pain (traumatic, diabetic, metabolic, infectious or toxic pain and pain caused by anticancer drugs or iatrogenic treatment) (Bone) joint pain, rheumatic pain, fibromyalgia, back pain, cancer pain, facial neuralgia, headache, migraine, toothache, burns, sunburn, animal bites or insect stings, postherpetic neuralgia, muscle pain, nerve Prevention of seizure (central and / or peripheral), spinal and / or brain trauma, ischemia (spinous and / or brain), neurodegeneration, hemorrhagic stroke (spinous and / or brain) and post-seizure pain and / Or in treatment.

  The compounds of the present invention prevent and / or treat urinary disorders such as bladder hyperactivity, bladder reflex, bladder instability, incontinence, frequent urinary incontinence, cystitis, renal colic, pelvic hyperfunction and pelvic pain. Can be used to prepare a drug for

  The compounds of the present invention can be used to prepare a medicament for the prevention and / or treatment of gynecological disorders such as pain associated with vulvar lesions and tubal inflammation or with dysmenorrhea.

  These products can cause gastrointestinal reflux disorders, gastric ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS (irritable bowel syndrome), Crohn's disease, pancreatitis, esophagitis and gallstone colic and other gastrointestinal disorders It can also be used to prepare a medicament for prevention and / or treatment.

  Similarly, the products of the present invention may be useful in preventing and / or treating respiratory disorders such as asthma, cough, COPD (chronic obstructive pulmonary disease), bronchoconstriction and inflammatory disorders. These products can also be used to prevent and / or treat psoriasis, pruritus, cutaneous, ocular or mucosal inflammation, herpes zoster and herpes zoster.

  The compounds of the present invention can also be used to prepare a medicament for treating depression.

  The compounds of the present invention can also be used to prepare a medicament for treating diabetes.

  According to another aspect of the present invention, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention as an active agent. This pharmaceutical composition comprises an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and also at least one pharmaceutically acceptable dosage. Contains a dosage form.

  Such excipients are selected from conventional excipients known to those skilled in the art, depending on the pharmaceutical dosage form and the desired mode of administration.

  In the pharmaceutical composition for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, or rectal administration of the present invention, the active agent of the above formula (I) or its may be considered. Salts, solvates or hydrates may be administered to humans and animals in unit dosage form as a mixture with standard pharmaceutical excipients to prevent or treat the disorders or diseases described above. it can.

  Suitable unit dosage forms for administration include tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, ocular Dosage forms for internal and intranasal administration, dosage forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms and implants. For topical use, the compounds according to the invention can be used in creams, gels, pomades or lotions.

By way of example, a unit dosage form of administration of a compound according to the invention in the form of a tablet may comprise the following components:
50.0 mg of the compound according to the invention
Mannitol 223.75mg
Sodium croscarmellose 6.0mg
Corn starch 15.0mg
Hydroxymethylcellulose 2.25mg
Magnesium stearate 3.0mg
Such unit dosage forms are dosed according to the Gallen Pharmaceutical dosage form to administer 0.001-30 mg of active ingredient per kg of body weight per day.

  There may be special cases where higher or lower dosages are appropriate. Such dosages do not depart from the scope of the invention. According to normal practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and sensitivity of the patient.

  According to another aspect of the present invention, the present invention also relates to a method for the treatment of the diseases mentioned above, which method comprises the step of giving the patient a compound according to the invention or a pharmaceutically acceptable salt thereof, Or administering an effective dose of a hydrate or solvate.

Claims (8)

Compound of general formula (I)

[Where:
X ₁ , X ₂ , X ₃ and X ₄ each independently represent a hydrogen atom or a halogen atom or a C ₁ -C ₆ -alkyl, C ₁ -C ₆ -fluoroalkyl or NR ₁ R ₂ group, ₁ and R ₂ are C ₁ -C ₆ -alkyl;
W is a formula bonded to the nitrogen atom at position 2 or 3:

And W is selected from a benzimidazolyl, indolyl, benzothiazolyl, quinolyl, tetrahydroquinolyl or benzoxazinyl group;
The carbon atom (s) of A may be substituted with one or more C ₁ -C ₆ -alkyl, C ₁ -C ₆ -fluoroalkyl, C ₃ -C ₇ -cycloalkyl or oxo groups Often;
The nitrogen atom (s) of A may be substituted with R ₆ when the nitrogen is adjacent to a carbon atom substituted with an oxo group, where R ₆ is a hydrogen atom or C ₁ -C ₆ -alkyl. represents a group; or otherwise may be substituted by _{R 7, R 7} is _C 1 -C ₆ - alkyl or _C 3 -C ₇ - cycloalkyl _-C 1 -C ₃ - alkylene group Represents;
n represents 1 or 2; and Y represents a heteroaryl selected from a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazolyl, benzothiazolyl, thiazolyl, furyl, quinolyl, isoquinolyl, quinoxalinyl group, and this heteroaryl Is substituted with one or more groups selected from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -fluoroalkyl, aryl-C ₁ -C ₆ -alkylene and NR ₁ R ₂ groups Alternatively, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a morpholinyl group. ]
Or a pharmaceutically acceptable base or acid addition salt, hydrate or solvate thereof. Formula (IV)

[Wherein, X ₁ , X ₂ , X ₃ , X ₄ , Y and n are the same as defined in the general formula (I) according to claim 1, and B represents C ₁ -C ₆ -alkoxy] Represents a group. ]
Of the general formula (V)

[Wherein W is the same as defined in formula (I) described in claim 1. ]
A process for preparing a compound of general formula (I) according to claim 1, characterized in that it is reacted with an amine compound of Compounds of general formula (IV) selected from the following compounds:
Ethyl 5-fluoro-1-[(thiazol-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(pyrid-3-yl) ethyl] -1H-indole-2-carboxylate Ethyl 5-fluoro-1-[(pyrid-3-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(pyrid-4-yl) methyl] -1H-indole-2 -Ethyl carboxylate 5-fluoro-1-[(pyrid-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(2-methylpyrid-3-yl) methyl] -1H -Ethyl indole-2-carboxylate 5-fluoro-1-[(1-N-benzylimidazol-2-yl) methyl] -1H-ethyl 2-indole-2-carboxylate 5-Fluoro Rho-1-[(2-Pyrrolidinopyrid-3-yl) methyl] -1H-indole-2-carboxylate 5-Fluoro-1-[(benzothiazol-2-yl) methyl] -1H-indole-2- Ethyl carboxylate 5-fluoro-1-[(1-methylbenzimidazol-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(4-methylthiazol-5-yl) Ethyl] -1H-indole-2-carboxylate ethyl 5-fluoro-1-[(quinol-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(quinoxaline-2- Yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(pyrazin-2-yl) methyl] -1H-indole-2-ca Ethyl borate 5-fluoro-1-[(3-methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(isoquinol-1-yl) methyl] -1H- Ethyl indole-2-carboxylate 5-fluoro-1-[(4-methylpyrid-2-yl) methyl] -1H-ethyl indole-2-carboxylate 5-fluoro-1-[(2-methylpyrid-4-yl ) Ethyl] -1H-indole-2-carboxylate ethyl 5-fluoro-1-[(2-methylpyrid-4-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(5 -Methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(dimethylpyrazin-2-yl) methyl] -1H Ethyl indole-2-carboxylate 5-fluoro-1-[(6-methylpyrazin-2-yl) methyl] -1H-ethyl indole-2-carboxylate 5-fluoro-1-[(6-methylpyridazine-3 -Yl) methyl] -1H-ethyl indole-2-carboxylate 5-fluoro-1-[(6-methylpyrid-2-yl) methyl] -1H-ethyl 2-indole-2-carboxylate 5-fluoro-1- [ (2-Phenylpyrid-4-yl) methyl] -1H-indole-2-carboxylate ethyl 6-t-butyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate 5 -Trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate 6-N-dimethylamino-1-[(pyrido- -Yl) methyl] -1H-indole-2-carboxylate ethyl 6-trifluoromethyl-1-[(pyrid-4-yl) methyl] -1H-indole-2-carboxylate methyl 5-t-butyl-1 -Ethyl [(pyrid-4-yl) methyl] -1H-indole-2-carboxylate 5-terbutyl-1-[(pyrid-2-yl) methyl] -1H-ethyl 2-indole-2-carboxylate 5-terbutyl -1-[(Pyrid-3-yl) methyl] -1H-indole-2-carboxylic acid ethyl 5-terbutyl-1-[(2-methylpyrid-3-yl) methyl] -1H-indole-2-carboxylic acid Ethyl 5-terbutyl-1-[(6-methylpyrid-2-yl) methyl] -1H-indole-2-carboxylate 5-fluoro-1-[(pyrimidine-4 -Yl) methyl] -1H-indole-2-carboxylate, or a pharmaceutically acceptable base or acid addition salt, hydrate or solvate thereof. Compounds of general formula (V) selected from the following compounds:
5-amino-1- (cyclopropyl) methyl-2-methyl-1H-benzimidazole 5-amino-2-cyclopropyl-1-methyl-1H-benzimidazole 5-amino-2-isopropyl-1-methyl-1H -Benzimidazole 6-amino-1- (cyclopropyl) methyl-2-methyl-1H-benzimidazole 6-amino-2-cyclopropyl-1-methyl-1H-benzimidazole 6-amino-2-isopropyl-1- Methyl-1H-benzimidazole, or a pharmaceutically acceptable base or acid addition salt, hydrate or solvate thereof. A compound of general formula (I) according to claim 1 (except for the compound of general formula (I) wherein Y is furyl) , or a pharmaceutically acceptable salt thereof, or alternatively a hydrate or A drug comprising a solvate. A compound of general formula (I) according to claim 1 (except for the compound of general formula (I) wherein Y is furyl) , or a pharmaceutically acceptable salt, hydrate or solvate thereof, And further comprising at least one pharmaceutically acceptable excipient. A compound of general formula (I) according to claim 1 for preparing a medicament for preventing or treating a disease associated with a receptor of TRPV1 type (wherein Y is Except for compounds that are furyl) . To prevent or treat pain, inflammation, urological disorders, gynecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritus, skin, eye or mucosal hypersensitivity, herpes or herpes zoster, or depression or diabetes Use of a compound of general formula (I) according to claim 7 (except for the compound of general formula (I) wherein Y is furyl) for the preparation of a medicament for treatment.